1. Alsaqati M, Heine VM, Harwood AJ. {{Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation}}. {Mol Autism}. 2020; 11(1): 80.
BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. METHODS: Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. RESULTS: We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. LIMITATIONS: Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. CONCLUSIONS: Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.
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2. Engelhard MM, Berchuck SI, Garg J, Henao R, Olson A, Rusincovitch S, Dawson G, Kollins SH. {{Health system utilization before age 1 among children later diagnosed with autism or ADHD}}. {Sci Rep}. 2020; 10(1): 17677.
Children with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD) have 2-3 times increased healthcare utilization and annual costs once diagnosed, but little is known about their utilization patterns early in life. Quantifying their early health system utilization could uncover condition-specific health trajectories to facilitate earlier detection and intervention. Patients born 10/1/2006-10/1/2016 with ≥ 2 well-child visits within the Duke University Health System before age 1 were grouped as ASD, ADHD, ASD + ADHD, or No Diagnosis using retrospective billing codes. An additional comparison group was defined by later upper respiratory infection diagnosis. Adjusted odds ratios (AOR) for hospital admissions, procedures, emergency department (ED) visits, and outpatient clinic encounters before age 1 were compared between groups via logistic regression models. Length of hospital encounters were compared between groups via Mann-Whitney U test. In total, 29,929 patients met study criteria (ASD N = 343; ADHD N = 1175; ASD + ADHD N = 140). ASD was associated with increased procedures (AOR = 1.5, p < 0.001), including intubation and ventilation (AOR = 2.4, p < 0.001); and outpatient specialty care, including physical therapy (AOR = 3.5, p < 0.001) and ophthalmology (AOR = 3.1, p < 0.001). ADHD was associated with increased procedures (AOR = 1.41, p < 0.001), including blood transfusion (AOR = 4.7, p < 0.001); hospital admission (AOR = 1.60, p < 0.001); and ED visits (AOR = 1.58, p < 0.001). Median length of stay was increased after birth in ASD (+ 6.5 h, p < 0.001) and ADHD (+ 3.8 h, p < 0.001), and after non-birth admission in ADHD (+ 1.1 d, p < 0.001) and ASD + ADHD (+ 2.4 d, p = 0.003). Each condition was associated with increased health system utilization and distinctive patterns of utilization before age 1. Recognizing these patterns may contribute to earlier detection and intervention. Lien vers le texte intégral (Open Access ou abonnement)
3. Gonzales-Rojas R, Rana AN, Mason P, Renfro C, Annaluru V, Panda S, Lee HY. {{The mouse model of fragile X syndrome exhibits deficits in contagious itch behavior}}. {Sci Rep}. 2020; 10(1): 17679.
Individuals with autism spectrum disorders (ASDs) imitate observed behavior less than age-matched and typically developing peers, resulting in deterred learning ability and social interaction. However, this deficit lacks preclinical assessment tools. A previous study has shown that mice exhibit contagious itch behavior while viewing a scratching demonstrator mouse, as opposed to an ambulating demonstrator mouse, but whether autism mouse models imitate observed scratching behavior remains unknown. Here, we investigated contagious itch behavior in the mouse model of fragile X syndrome (FXS), a common form of inherited intellectual disabilities with a high risk for ASDs. We found that the mouse model of FXS shows deficits in contagious itch behavior. Our findings can be used as a new preclinical assessment tool for measuring imitative deficits in the study of neurodevelopmental disorders including FXS.
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4. Gordon-Lipkin E, Hoon A, Pardo CA. {{Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future}}. {Dev Med Child Neurol}. 2020.
Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable.
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5. Kaliukhovich DA, Manyakov NV, Bangerter A, Ness S, Skalkin A, Goodwin MS, Dawson G, Hendren RL, Leventhal B, Hudac CM, Bradshaw J, Shic F, Pandina G. {{Social attention to activities in children and adults with autism spectrum disorder: effects of context and age}}. {Mol Autism}. 2020; 11(1): 79.
BACKGROUND: Diminished visual monitoring of faces and activities of others is an early feature of autism spectrum disorder (ASD). It is uncertain whether deficits in activity monitoring, identified using a homogeneous set of stimuli, persist throughout the lifespan in ASD, and thus, whether they could serve as a biological indicator (« biomarker ») of ASD. We investigated differences in visual attention during activity monitoring in children and adult participants with autism compared to a control group of participants without autism. METHODS: Eye movements of participants with autism (n = 122; mean age [SD] = 14.5 [8.0] years) and typically developing (TD) controls (n = 40, age = 16.4 [13.3] years) were recorded while they viewed a series of videos depicting two female actors conversing while interacting with their hands over a shared task. Actors either continuously focused their gaze on each other’s face (mutual gaze) or on the shared activity area (shared focus). Mean percentage looking time was computed for the activity area, actors’ heads, and their bodies. RESULTS: Compared to TD participants, participants with ASD looked longer at the activity area (mean % looking time: 58.5% vs. 53.8%, p < 0.005) but less at the heads (15.2% vs. 23.7%, p < 0.0001). Additionally, within-group differences in looking time were observed between the mutual gaze and shared focus conditions in both participants without ASD (activity: Δ = - 6.4%, p < 0.004; heads: Δ = + 3.5%, p < 0.02) and participants with ASD (bodies: Δ = + 1.6%, p < 0.002). LIMITATIONS: The TD participants were not as well characterized as the participants with ASD. Inclusion criteria regarding the cognitive ability [intelligence quotient (IQ) > 60] limited the ability to include individuals with substantial intellectual disability. CONCLUSIONS: Differences in attention to faces could constitute a feature discriminative between individuals with and without ASD across the lifespan, whereas between-group differences in looking at activities may shift with development. These findings may have applications in the search for underlying biological indicators specific to ASD. Trial registration ClinicalTrials.gov identifier NCT02668991.
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6. Kaltenegger HC, Doering S, Gillberg C, Wennberg P, Lundström S. {{Low prevalence of risk drinking in adolescents and young adults with autism spectrum problems}}. {Addictive behaviors}. 2020; 113: 106671.
Individuals with Autism Spectrum Disorder (ASD) have high rates of « comorbidity ». Research on concurrent substance use (disorder) in ASD, however, is scarce and findings have been inconsistent. This study aims at assessing the prevalence of risk drinking in adolescent and young adult twins with and without autism spectrum problems. Data from a Swedish longitudinal nationwide twin study were analyzed. Across three age groups of 15- (N = 10,050), 18- (N = 7,931) and 24-year-olds (N = 2,882) prevalence rates of risk drinking were compared between twins with and without an ASD proxy diagnosis and between different ASD subgroups based on comorbid proxies for attention-deficit/hyperactivity disorder (ADHD) and/or Learning Disorder (LD). ASD, ADHD, and LD were assessed using the Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC), and risk drinking was captured by the Alcohol Use Disorders Identification Test (AUDIT; age 18 and 24) and another set of self-report questions (age 15). In each age group, the prevalence of risk drinking in ASD was lower than in individuals without ASD, yet increasing continuously with age. Exploratory subgroup ASD analyses showed a trend towards risk drinking being more common among individuals with co-existing ADHD or LD problems than among those without « comorbidity », although sample sizes were too small to draw any certain conclusions. This study indicates low prevalence of risk drinking in adolescents and young adults with autism spectrum problems and highlights the need for further research on alcohol use in individuals with ASD and comorbid disorders.
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7. Kerub O, Haas EJ, Meiri G, Bilenko N, Flusser H, Michaelovski A, Dinstein I, Davidovitch N, Menashe I. {{Ethnic Disparities in the Diagnosis of Autism in Southern Israel}}. {Autism Res}. 2020.
The prevalence of autism spectrum disorder (ASD) is continuously rising worldwide, with remarkable differences in ASD rates being reported across ethnic and socioeconomic groups. We conducted a prospective cohort study to identify the reasons for differences in ASD rates between the Bedouin and Jewish populations in southern Israel. Screening, referral, and diagnosis of toddlers aged 16-36 months were compared between Bedouin and Jewish populations. ASD screening was conducted at 35 randomly selected mother and child health centers (MCHCs) by trained nurses using the Modified Checklist for Autism in Toddlers with follow-up (M-CHAT/F) instrument. Toddlers screened positive at the MCHCs were monitored throughout the referral and diagnosis process at a single medical center until a diagnosis was determined by a physician specialist using DSM-5 criteria. The study cohort comprised 3,343 toddlers (996 Jewish and 2,347 Bedouin). Bedouin toddlers, compared to Jewish toddlers, were less likely to screen positive with M-CHAT/F (3.0% vs. 3.9%; P = 0.165), were significantly less likely to begin the hospital diagnosis process (HR = 0.38, 95% CI: 0.14-1.08; P = 0.068), and had a higher rates of loss-to-follow-up during the hospital diagnosis process (42.9% vs. 15.6%, respectively; P = 0.001). The results suggest that ethnic-specific barriers in the diagnosis process of ASD contribute to under-diagnosis of ASD in the Bedouin population. Facilitating the diagnosis process for Bedouin families will help to identify more children with ASD at earlier ages and consequently close the ethnic gap in ASD rates. LAY SUMMARY: We followed Bedouin and Jewish toddlers aged 16-36 months from southern Israel through their autism spectrum disorder (ASD) screening referral and diagnosis to identify the reasons for the differences in ASD prevalence between these ethnic groups. Jewish and Bedouin toddlers were equally identified in the ASD screening. However, Bedouin toddlers were less likely to complete the diagnosis process due to higher rates of loss-to-follow-up and slower diagnosis process. Facilitating ASD diagnosis for the Bedouin population will help identifying more toddlers with ASD.
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8. Khalid M, Raza H, T MD, P JL, Tejwani L, Sami A, Nawaz M, Mehmood Baig S, Lim J, Kaukab Raja G. {{Genetic Risk of Autism Spectrum Disorder in a Pakistani Population}}. {Genes}. 2020; 11(10).
Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, and genome-wide association studies (GWAS). However, associations between different SNPs and ASD vary from population to population. Four SNPs in genes CNTNAP2, EIF4E, ATP2B2, CACNA1C, and SNP rs4307059 (which is found between CDH9 and CDH10 genes) have been identified and reported as candidate risk factors for ASD. The aim of the present study was, for the first time, to assess the association of SNPs in these genes with ASD in the Pakistani population. PCR-based genotyping was performed using allele-specific primers in 93 ASD and 93 control Pakistani individuals. All genetic associations, genotype frequencies, and allele frequencies were computed as odds’ ratios (ORs) using logistic regression with a threshold of p ≤ 0.01 to determine statistical significance. We found that the homozygous genotypes of mutant T alleles of CNTNAP2 and ATP2B2 were significantly associated with Pakistani ASD patients in unadjusted ORs (p < 0.01), but their significance score was lost in the adjusted model. Other SNPs such as rs4307059, rs17850950 of EIF4E, and rs1006737 of CACNA1C were not statistically significant. Based on this, we conclude that SNPs are not associated with, or are not the main cause of, autism in the Pakistani population, indicating the involvement of additional players, which need to be investigated in future studies in a large population size. One of the limitations of present study is its small sample size. However, this study, being the first on Pakistani ASD patients, may lay the foundations for future studies in larger samples. Lien vers le texte intégral (Open Access ou abonnement)
9. Leifler E, Carpelan G, Zakrevska A, Bölte S, Jonsson U. {{Does the learning environment ‘make the grade’? A systematic review of accommodations for children on the autism spectrum in mainstream school}}. {Scandinavian journal of occupational therapy}. 2020: 1-16.
BACKGROUND: The 2030 Agenda for Sustainable Development adapted by the United Nations envisions inclusive and equitable quality education. While there is a growing body of research on interventions designed to help children on the autism spectrum adapt to the school environment, accommodations to children needs have been given less attention. OBJECTIVE: To synthesize the literature on accommodations in the learning environment for children on the autism spectrum (ages 5-19 years) in mainstream school, with a specific focus on the effects on functioning, educational outcomes and well-being. METHODS: A systematic search was conducted. The study selection and data extraction were performed by two independent reviewers. Eligible studies were assessed according to the What Works Clearinghouse (WWC) standards. RESULTS: The search yielded 6102 citations. Only 37 eligible studies were identified, of which 14 met the WWC standards. This inconclusive and heterogeneous body of research tentatively suggest that accommodations in the pedagogical and psychosocial leaning environment can improve performance and function in school. CONCLUSION AND SIGNIFICANCE: Accommodations in the learning environment is a promising but understudied approach. Creative research and innovation will be needed to support policy makers and school personnel in their quest to ensure inclusive and equitable education.
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10. Malhi P, Venkatesh L, Bharti B, Singhi P. {{Do Atypical Food Preferences in Children with Autism Differ by Severity?}}. {Indian journal of pediatrics}. 2020.
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11. Minio-Paluello I, Porciello G, Pascual-Leone A, Baron-Cohen S. {{Face individual identity recognition: a potential endophenotype in autism}}. {Mol Autism}. 2020; 11(1): 81.
BACKGROUND: Face individual identity recognition skill is heritable and independent of intellectual ability. Difficulties in face individual identity recognition are present in autistic individuals and their family members and are possibly linked to oxytocin polymorphisms in families with an autistic child. While it is reported that developmental prosopagnosia (i.e., impaired face identity recognition) occurs in 2-3% of the general population, no prosopagnosia prevalence estimate is available for autism. Furthermore, an autism within-group approach has not been reported towards characterizing impaired face memory and to investigate its possible links to social and communication difficulties. METHODS: The present study estimated the prevalence of prosopagnosia in 80 autistic adults with no intellectual disability, investigated its cognitive characteristics and links to autism symptoms’ severity, personality traits, and mental state understanding from the eye region by using standardized tests and questionnaires. RESULTS: More than one third of autistic participants showed prosopagnosia. Their face memory skill was not associated with their symptom’s severity, empathy, alexithymia, or general intelligence. Face identity recognition was instead linked to mental state recognition from the eye region only in autistic individuals who had prosopagnosia, and this relationship did not depend on participants’ basic face perception skills. Importantly, we found that autistic participants were not aware of their face memory skills. LIMITATIONS: We did not test an epidemiological sample, and additional work is necessary to establish whether these results generalize to the entire autism spectrum. CONCLUSIONS: Impaired face individual identity recognition meets the criteria to be a potential endophenotype in autism. In the future, testing for face memory could be used to stratify autistic individuals into genetically meaningful subgroups and be translatable to autism animal models.
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12. Moreau CA, Urchs SGW, Kuldeep K, Orban P, Schramm C, Dumas G, Labbe A, Huguet G, Douard E, Quirion PO, Lin A, Kushan L, Grot S, Luck D, Mendrek A, Potvin S, Stip E, Bourgeron T, Evans AC, Bearden CE, Bellec P, Jacquemont S. {{Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia}}. {Nat Commun}. 2020; 11(1): 5272.
16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.
